Project Summary/Abstract Physical Sciences Inc. in collaboration with the University of Connecticut School of Pharmacy proposes to develop both hardware and software tools that will support Quality by Design based development of freeze drying processes for co-solvent product formulations. Co-solvent systems (water plus a single organic solvent) are used in freeze drying particularly when the drug degrades in pure water during upstream processing such as compounding, aseptic filling, loading and freezing (e.g., bendamustine, alprostadil, and many peptide drugs). Degradation may also occur when the drug formulation is not sufficiently soluble in pure water (e.g., processing of self-assembled nanocarriers with drug). Unfortunately there are very few tools that aid process engineers in developing lyophilization cycles for these co-solvent formulations. PSI and UConn will develop a Tunable Diode Laser Absorption Spectroscopy based co-solvent mass flow rate monitor and a steady state heat and mass transfer model of vial-based freeze drying to enable efficient development and verification of co-solvent freeze drying cycles based on product temperature requirements. During the Phase I effort PSI will focus on the development and testing of an organic solvent mass flow rate monitor. The non-contact, real-time sensor measurement of the integrated amount of solvent removed will be compared to gravimetric determinations of solvent removed. Following sensor feasibility testing the Process Analytical Technology tool will be used to measure Key Process Parameters that enable use of the heat and mass transfer model developed by UConn to calculate process knowledge and design spaces to maintain a required product temperature. The model predicted mass flow rates for solvent sublimation will be compared to sensor measurements to upgrade and verify model performance. During subsequent R&D efforts the sensor and model products will be matured and further verified by designing and running lyophilization processes which are monitored for product collapse and melt-back, which may occur when operating the process with a product temperature above the collapse temperature or transitioning from primary to secondary drying before all of the vials have completed ice sublimation. In addition, we anticipate creating algorithms that support the automation of co-solvent cycle development and testing in both laboratory and pilot scale freeze dryers. The proposed effort supports the US FDA Process Analytical Technology and Regulatory Science initiatives by developing tools that can be directly used to infer information that affects product quality during processing, the product temperature. The combined use of the proposed sensor and mathematical model will allow end users to predict and verify freeze drying cycle performance. The proposed effort has support of a well-known industry equipment supplier and large pharmaceutical companies.